Thiaxanthone-10,10-dioxides

ABSTRACT

WHEREIN Y is hydrogen, halo, alkyl, NO2, perfluoroalkyl, cyano, PO-, RSO2-, R2NSO2-, R2NCO- (R being alkyl, aryl, aralkyl, alkaryl or hydrogen); and R2 is alkyl, aryl, aralkyl, alkaryl or hydrogen and R3 is alkyl, aralkyl or hydrogen. The disclosed process is summarized in the flow sheet at pages 2-3 of the specification. The compounds exhibit anti-anxiety activity and a depressant effect on the central nervous system.   This invention pertains to pharmacologically active compounds of the following structure:

United States Patent Engelhardt et al.

[54] THIAXANTHONE-l0,l0-DIOXIDES [72] Inventors: Edward L. Engelhardt, Gwynedd Valley; David C. Remy, North Wales, both of Pa.

[73] Assignee: Merck 8: Co., Inc., Rahway, NJ.

[22] Filed: March 19, 1970 [21] Appl. No.: 21,795

Related U.S. Application Data [62] Division of Ser. No. 661,784, Aug. 21, 1967,

Pat. No. 3,530,116.

[52] U.S. Cl ..260/328 [51] Int. Cl. ..A6lk 27/00, C07d 65/18 [58] Field of Search ..260/328 [56] References Cited UNITED STATES PATENTS 2,884,300 4/1959 Braun et a1. ..8/55 3,530,116 9/1970 Engelhardt et a1. ....260/239.3

FOREIGN PATENTS OR APPLICATIONS 781,558 8/1957 Great Britain ..260/328 I451 Oct. 10, 1972 Primary Examiner-Henry R. .Iiles Assistant Examiner-Cecilia M. Shurko Attorney-'Ihomas E. Arther, Harry E. Westlake, Jr. and 1. Louis Wolk [57] ABSTRACT This invention pertains to pharmacologically active compounds of the following structure:

Y .Y W

wherein Y is hydrogen, halo, alkyl, N0 perfluoroalkyl, cyano, PO, RSO R NSO R NCO (R being alkyl, aryl, aralkyl, alkaryl or hydrogen); and R is alkyl, aryl, aralkyl, alkaryl or hydrogen and R is alkyl, aralkyl or hydrogen. The disclosed process is summarized in the flow sheet at pages 2-3 of the specification. The compounds exhibit anti-anxiety activity and a depressant effect on the central nervous system.

9 Claims, No Drawings THIAXANTHONE-10,10-DIOXIDES This application is a division of application, Ser. No. 661,784, filed Aug. 2i, 1967, now U.S. Pat. No. 0,.l.

FIELD OF THE INVENTION I BRIEF SUMMARY OF THE INVENTION The novel compounds of this invention can be 15 r essatsib isrmslats. a--.

DETAILED DESCRIPTION OF THE INVENTION The compounds of this invention are prepared from starting materials which are either well known or which are all themselves prepared from readily available compounds according to procedures apparent to the artskilled. The general procedures for obtaining com- .pound I are outlined in steps (A) through (E).

In the following reaction sequence R and Y are as previously defined; R is alkyl, aralkyl or alkaryl; X is halo; X is chlorine or bromine, and X is chlorine, bromine or iodine. It is preferred that the alkyl groups be lower alkyl (i.e., methyl, ethyl, n-propyl, i-propyl, nbutyl, t-butyl, sec-butyl). Usually the aryl moiety is mononuclear, e.g., phenyl; but polynuclear aryls, such as napthyl, phenanthryl, anthryl, etc. are within the contemplation of this invention. Preferably the aralkyl, alkaryl, and aryl moieties contain up to about ten carbons. It is also preferred that the halogen be chlorine or bromine.

A Bl

B O O Y u hydrolysis C O O Y (IV) XIRICHCOX' HGOHR X O O Y reflux liquid ammonia NHEIJCHRJXI 3O ogg Y NH([3CHRNH2 E O O Y N H R 1'1 0 Step A involves the replacement of the l-halo substituent with a substituted sulfonyl amino group having the general formula H N 50 R (wherein R is as previously defined). Generally this reaction step is carried out in an inert high boiling solvent preferably having a boiling point from about 180 C. to about 250 C., such as nitrobenzene, and using a catalytic agent, such as copper powder, which is the conventional reagent, in the presence of bases, such as sodium acetate, potassium acetate, alkali metal carbonates and other similar 0 weak bases.

Step B This step comprises a conventional hydrolysis in the presence of a strong acid, such as sulfuric acid, and isgenerally carried out by dissolving the sulfonamide derivative (III) in the heated sulfuric acid followed by quenching in ice. Other strong acids can be employed such as phosphoric and concentrated hydrochloric acid.

Step C Following hydrolysis, the amine (IV) is reacted with an alpha-halo acyl halide of the formula defined). This acylation step involves various methods for removal of the hydrogen halide that is formed, such as combining with a base, such as pyridine, or expelling it as a gas. Various inert organic solvents can be employed. Where pyridine is utilized as the receptor for the hydrogen halide, ether can be employed as a solvent, for example. Where the halide is expelled as a gas, the reaction can be carried out in a solvent, such as benzene, toluene and a wide variety of other inert organic solvents. When an organic base is utilized to neutralize the hydrogen halide, at least one equivalent of the organic base should be employed as the receptor in order to remove allof the hydrogen halide being.

given off in the reaction and thereby avoid the formation of quaternary salts. The amination is effected by suspending (V) inliquid ammonia and allowing it to reflux under stirring for a sufficient period of time to allow the reaction to proceed to completion. This can be a matter of from one hour to a day.

Step E This conventional condensation proceeds.

straightforwardly. For example, where Y is methyl, all

that is necessary to effect the condensation and ring, closure is melting the crystalline material (VI); in otherinstances, it may be necessary to effect the reaction under refluxing conditions in such solvents as pyridine and the like. The duration of the reaction dependsi upon the molecule employed and can be anywhere from a matter of hours to a matter of days for completion..

The foregoing. reaction sequence produces compounds of the Formula (I) wherein R is hydrogen. (Designated In the above reaction sequence). To prepare compounds wherein R is alkyl or aralkyl, introduction of such a R group into the benzodiazepin Ia can be accomplished according to the method of L. H. Sternback, et al., J. Org. Chem...27, 3788; (1962) and a PF: rsprsssat s xthefsi l i 'l sme iqm i (fr; R2 E EXAMPLE I l ,4-Dichlorothiaxanthone-I 0,10-dioxide I l,4-Dichlorothiaxanthone (5.5 g.) is suspended in 40 ml. of glacialacetic acid. The mixture is stirred while 4 ml. of 30 percent hydrogen peroxide is added. The mix- ;ture is heated to reflux at a gentle boil for one hour and then allowed to cool overnight. j The next morning the mixture is cooled in an ice bath and filtered. The precipitateis washed with 25 ml. of f'acetic acid and dried overnight at 65. The mother iliquor from the filtration is diluted with 50 ml. of water and the mixture cooled overnight. The precipitated %crystals are filtered, washed with acetic acid and dried in a similar manner. The product after recrystallization Efrem glacial acetic acid melts at l83.6 to 185 C. and is I ,4-dichlorothiaxanthonel0, l O-dioxide.

EXAMPLE ll A. l -p-Toluenesulfonamido-4-chlorothiaxanthone- 10,10-dioxide into a flask fitted with a stirrer and a condenser topped with a calcium chloride drying tube is charged E100 mg. of copper powder, 8.35 g. of paratoluenesub lfonamide, 4.05 g. of anhydrous potassium acetate,

$10.16 g. of l,4-dichlorothiaxanthone-l0,l0-dioxide' land 60ml. of nitrobenzene. The mixture is stirred at gentle reflux for 10 hours and then allowed to cool. The nitrobenzene is steam distilled out and the residue is filltered from the boiling water. The residue is ground to a "powder and recrystallized once from acetic acid. The product is dried and found to melt at 199 205 C.

B. l -Amino-4-chlorothiazanthone-10,1 Odioxide l -p-Toluenesulfonamido-4-chlorothiaxanthonel0,l0-dioxide (2 g.) is placed in a 50 ml. flask fitted with a magnetic stirrer and a drying tube. 20 ml. of concentrated sulfuric acid is added and the mixture is heated on a steam bath for one hour, after which it is cooled to room temperature and drowned in 200 ml. of water. The mixture is diluted with IO-normal sodium hydroxide until quite basic (pl-l 9-10) and the product is isolated by filtration and washed with water and dried. After two recrystallizations from benzene -the product melts at 2l4.5-2l7 C. C. l-Bromoacetamido-4-chlorothiaxanthonel 0, l 0- dioxide Into a flask fitted with a reflux condenser and a drying tube is charged 0.285 g. of dry pyridine, 1.025 g. of l-amino-4-chlorothiaxanthone-l0,l0 dioxide, 0.725 g. of bromoacetylbromide and 100 ml. of dry ether. The mixture is stirred for 24 hours and then filtered. The precipitate is washed with ether and then with water after which it is suspended in 200ml; of water, filtered, and washed with ether. After the product is. dried it melts at 2082l0.5 C. with softening at l-202 C. D. l-Aminoacetamido-4-chlorothiaxanthonel 0, l0- dioxide lnto a flask fitted with a stirrer, gas inlet and dry ice condenser is charged 1.09 g. of l-bromoacetamido-4- chlorothiaxanthone-lOJO-dioxide and ml. of liquid ammonia is condensed into the flask. The mix,- ture is then stirred for 6 hours after which the ammonia is allowed to evaporate. Water is then added and the mixture is stirred for 2 hours. The precipitate is filtered off and is washed with water. After drying the product is recrystallized from benzene to produce 1- 29?senseless-9Pletethiae hqvzt ide m.p. 199-200C. Anal. Calcd for C,,H CIN,O S (350.80) 2 C, 51.36; H, 3.16; C1, 10.10; S, 9.14. Found: C, 51,57; H, 3.33, Cl, 9.90; S, 9.18. E. 7-Chloro-3(4H)-oxo-2H-thiaxanthono (9,9a,l-ef- 1 ,4-diazepin-8,8dioxide A solution of 0.86 g. of l-aminoacetamido-4- chlorothiaxanthone-10,10-dioxide and 10 ml. of pyridine is stirred magnetically and refluxed for 96 hours. The solution is evaporated to dryness in vacuo and the residue is co-evaporated with chloroform. The crude solid product is recrystallized several times from a mixture of water and dimethylformamide to give orange crystals of 7-chloro-3(4H)-oxo-2H-thiaxantheno (9,9a,1-ef)l,4-diazepin-8,8-dioxide, m.p. 288.7289.7 C. I Anal. Calcd for C,,H,C1H,O,S (332.78): C, 54.14; H, 2.73; Cl, 10.65; S, 9.64. Found: C, 54.10; H, 3.03; Cl, 10.52; S, 9.60.

EXAMPLE Ill A. 1 -p-Toluenesulfonamido-4-methylthiaxanthone- 10,10-dioxide Copper powder (167 mg), 7.11 g. of anhydrous potassium acetate, 14.70 g. of p-toluenesulfonamide, 106 ml. of nitrobenzene, and 16.77 g. of a mixture of 1- chloro-4-methylthiaxanthone-10,10-dioxide and lmethyl-4-chloro-thiaxanthone-10,10-dioxide [F. Ullmann and D. von Glenck, Ben, 49, 2487 (1916)] were added into a reaction flask provided with means for stirring, heating and refluxing. The mixture was heated to reflux for 10 hours, after which the reaction mixture was steam distilled to remove nitrobenzene. The hot water was decanted from a gummy brown pot residue. This residue was triturated with 100 ml. of hot glacial acetic acid to induce crystallization. The crystalline material was removed by filtration and washed with 200 ml. of glacial acetic acid. By fractional crystallization from glacial acetic acid, the unreacted 1-methy1-4- "chlorothiaxanthone-10,10-dioxide was removed and 12.4 g. of 1-(p-toluenesulfonamido)-4-methylthiaxanthone-10,10-dioxide was obtained as small yellowbrown needles, m.p. 203.2204.2 C. Anal. Calc'd for 21 1 sSz( 2. C, 59-9 :91. S 15: 9: Found: C, 58.98; H, 4.19; S, 15.01.

B. 1-Amino-4-methylthiaxanthone-10,10-dioxide 1-(p-Toluenesulfonamido)-4-methylthiaxanthone- 10,10-dioxide 12.21 g.) produced in step (A) and 130 ml. of concentrated sulfuric acid was placed in a 300 ml. reaction flask provided with a calcium chloride drying tube and magnetic stirrer. The mixture was heated on the steam bath for 1 hour while stirring, and then cooled to room temperature. The solution was then poured onto 1,300 ml. of ice and water. The mixture was stirred and made basic by addition of 520 ml. of N sodium hydroxide. The yellow precipitate was removed by filtration, collected, washed by suspension in 1 liter of water, and filtered. The dried product weighed 7.71 g. Recrystallization from benzene gave a red product identified as 1-amino-4-methylthiaxanthone-l0,10-dioxide, m.p. l91l92 C. Anal. Calcd for C H NO,S (273.30): C, 61.52; H, 4.06; S, 11.73.

Found: C, 61.79; H, 3.92; S, 11.64. C. 1 -Bromoacetamido-4-methylthiaxanthone-10,10- dioxide lnto a 100 ml. flask equipped with magnetic stirrer and condenser with a calcium chloride drying tube was placed 1.00 g. of 1-amino-4-chlorothiaxanthone-10,10-

6 dioxide, 0.30556? pyridinef ml. of ether, and 0.81 1 g. of bromoacetyl bromide. A yellow precipitate formed immediately and the orange crystals of starting material disappeared. The mixture was stirred overl-Aminoacetamido-4-methy1thiaxanthone-10, 10-

!B2xi,q... -WW

lnto a flask fitted with a stirrer, gas inlet and dry ice condenser was charged 0.50 g. of l-bromoacetamido- 4-methylthiaxanthone-l0,10-dioxide from part (C) and approximately ml. of liquid ammonia was condensed into the flask. The mixture was stirred for a minimum of 4 hours afterwhich theammonia was allowed to evaporate. To the yellow residue was added ml. of water and the mixture stirred to dissolve the ammonium bromide by-product. The mixture was filtered and the yellow product washed well with water,

collected, and dried to give 035 g. of product melting at l67-17l C., resolidifying at about l75180 C.

and remelting at 289292 C. (dec.). E. 7-Methyl 3-(4H)-oxo-2H-thiaxantheno (9,9a,l-ef)- 1 ,4-diazepin-8,8-dioxide l-Aminoacetamido-4-methylthiaxanthonel 0, l0- dioxide (200 mg.) was placed in a flask and immersed in a Woods metal bath at l80-185 C. for 15 minutes. The solid melted and then quickly re-solidified. This solid was purified by recrystallization from a mixture of water and dimethylformamide to give 7-methyl-3(4H)- oxo-2H-thiaxantheno (9,9a,1-ef)-l ,4-diazepin-8 ,8- dioxide as tiny orange plates, m.p. 292294 C. (dec.). Anal. Calcd for c,,r-i,,N,o,s (312.36): C, 61.53; H, 3.87; N, 8.97; S, 10.26. Found: C, 61.53; H, 3.97; N, 8.88; S, 10.38.

Using the appropriate starting compounds, the following products of Steps A through E are also prepared as above described:

STEP A Ex. Formula (11) H,NSO,R Product ([11) X Y R Y R 4 Br CH,O p-tolyl CH,O p-tolyl 5 1 NO, ethyl N0, ethyl 6 F CF, CH, CF, CH, 7 Cl H benzyl H benzyl 8 Cl CH,SO, CH, CH,S0, methyl 9 Cl 9: 3):

NSO, p-tolyl NSO, p-tolyl l0 BY (C 5): s):

NCO CH, NCO CH, 1 1 Cl CN n-propyl CN n-propyl 12 Cl Br CH, Br CH,

STEP B Example Formula [11 Product W Y R Y 12 CH,O p-tolyl CH,O 1 3 ethoxy ethyl ethoxy 14 NO, CH, N0, 15 ethyl sulfonyl benzyl ethyl sulfonyl l6 (C,H,),NSO, t-butyl (C,H,),NSO, l7 (CH,),NCO ch, (CH,),NCO 18 CN i-propyl CN STEPC FORMULA lV X'RCHCOX' PRODUCT V Ex. Y XFC X R Y X R 26 propoxy Cl Cl ethyl propoxy Cl ethyl 27 bltnxy Br Br butyl butoxy Br butyl 28 Cl Cl Br phenyl Cl Br phenyl 29 No, Cl Cl p-tolyl No, c1 p-tolyl 30 propyl- Cl Cl benzyl propyl Cl benzyl sulfonyl sulfonyl 3| (C,H,),. Cl I H (C,H,), l H

N80, 1 N80, 32 a s): P'QPY r x): P PY NCO NCO 33 CN cl Cl CH, CN Cl CH,

STEPD FORMULA V FORMULA Vl Ex. Y X R Y R' 34 propoxy Cl CH, propoxy CH, 35 butoxy Br ethyl butoxy ethyl 2O 36 Cl Br butyl Cl butyl 37 NO, Cl phenyl NO, phenyl 38 propyl Cl p-tolyl propylp-tolyl sulfonyl sulfonyl 39 |)r l H d- H NSO, N80, 40 (C,H,),- Cl propyl c,u, propyl 2 NCO NCO 41 CN Br CH, CN CH,

STEPE FORMULA Vl PRODUCT la Example Y R Y R 42 CH,O H CH,O H 43 NO, H N0, H 44 CF, phenyl CF, phenyl 45 H CH, H CH, 46 CH,SO, CH, CH,SO, CH, 47 (CH,), H (CH,), H

N80, N80, 48 (CH,), benzyl ((2H,), benzyl NCO NCO 49 CN p-tolyl CN p-tolyl 50 Br H Br H 5l l CH, l CH, 52 F H F H The compound of the present invention can be prepared and administered in a wide variety of oral and parenteral dosage forms, singly, or in combination with other coacting compounds. They can, if desired, be associated with a carrier which can be a solid material or a liquid in which the compound is dissolved, dispersed, or suspended. The solid compositions can take the form of tablets, powders, capsules, pills, or the like,

wherein Y is selected from hydrogen, halo, loweralkyl,

10 CN, NO,', trifluoromethyl, loweralkoxy, loweralkyl sulfonyl, diloweralkyl sulfamoyl, and diloweralkyl carbamoyl; and R is'selected from lower alkyl, benzyl and tolyl.

2. l-p-Toluenesulfonamido4-chlorothiaxanthonel 0, l O-dioxide.

3. l-p-Toluenesulfonamido-4-methylthiaxanthonel0 lO-dioxide.

QEQFEBQEEQPFFPEET'HFEL... H

wherein Y is selected from hydrogen, halo, loweralkyl, CN, NO,, trifluoromethyl, loweralkoxy, loweralkyl sulfonyl, diloweralkyl sulfamoyl, and diloweralkyl carbamoyl; R is selected from hydrogen, loweralkyl, phenyl, benzyl and tolyl; and X? is selected from 'chlorine, bromine and iodine.

5. l-Bromoacetamido-4-chlorothiaxanthonel 0, l0- dioxide.-

6. l -Bromoacetamido-4-methylthiaxanthonel 0, l0- dioxide.

7. A compound of the formula:

NBC CHR NH:

wherein Y is selected from hydrogen, halo, loweralkyl, CN, NO,, trifluoromethyl, loweralkoxy, loweralkyl sulfonyl, diloweralkyl sulfamoyl, and diloweralkyl car'-. 

2. 1-p-Toluenesulfonamido-4-chlorothiaxanthone-10,10-dioxide.
 3. 1-p-Toluenesulfonamido-4-methylthiaxanthone-10,10-dioxide.
 4. A compound of the formula
 5. 1-Bromoacetamido-4-chlorothiaxanthone-10,10-dioxide.
 6. 1-Bromoacetamido-4-methylthiaxanthone-10,10-dioxide.
 7. A compound of the formula:
 8. 1-Aminoacetamido-4-chlorothiaxanthone-10,10-dioxide.
 9. 1-Aminoacetamido-4-methylthiaxanthone-10,10-dioxide. 